Dimethylbenzofuran and dimethylbenzopyran derivatives and their use as 5-HT3 antagonists

ABSTRACT

Method of treating 5-HT 3  -mediated disorders, which comprises systemic administration of an effective amount of a compound of formula (I) ##STR1## the pharmaceutically acceptable acid addition salt forms and the stereochemically isomeric forms thereof, wherein R 1  and R 2  represent hydrogen, or R 1  and R 2  taken together form a bivalent radical of formula --CH═CH--CH═CH-- (a), --CH═C(Cl)--CH═CH--(b) or --CH═CH--C(Cl)=CH-- (c); n represents 2, 3 or 4; R 3  represents hydrogen or methoxy; m represents 1 or 2; R 4  represents hydrogen, amino or C 1-3  -alkylcarbonylamino; and R 5  represents hydrogen or halo; novel compounds; compositions; processes for preparing novel compounds and intermediates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 08/416,914,filed on Jun. 16, 1995, now U.S. Pat. No. 5,674,868, which in turn wasthe national stage of PCT Application Ser. No. PCT/EP 93/03206, filedNov. 15, 1993, which claims priority as a continuation-in-part from U.S.application Ser. No. 07/979,013, filed on Nov. 20, 1992.

BACKGROUND OF THE INVENTION

EP-0,389,037, published on Sep. 26, 1990 disclosesN-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran ordihydrobenzodioxin) carboxamide derivatives and EP-0,445,862, publishedon Sep. 11, 1991 discloses N-(4-piperidinyl)(dihydrobenzofuran ordihydrobenzo-2H-benzopyran)carboxamide derivatives. Both applicationsdisclose gastrointestinal motility stimulating properties for saidcompounds. The dimethyl-dihydrobenzofuran anddimethyl-dihydro-2H-benzo-pyran derivatives of the present inventionshow 5-HT₃ -antagonism.

DESCRIPTION OF THE INVENTION

The present invention is concerned with a method of treatingwarm-blooded animals suffering from 5-HT₃ mediated disorders such asanxiety, psychosis, depression, schizophrenia, cognitive disorders, drugabuse, migraine, emesis, irritable bowel syndrome and related disorders,which comprises the systemic administration to said warm-blooded animalsof an effective 5-HT₃ antagonistic amount of a compound of formula##STR2##

a pharmaceutically acceptable acid addition salt form or astereochemically isomeric form thereof, wherein

R¹ and R² represent hydrogen, or

R¹ and R² taken together form a bivalent radical of formula

--CH═CH--CH═CH-- (a),

--CH═C(Cl)--CH═CH-- (b) or

--CH═CH--C(Cl)═CH-- (c);

n represents 2, 3 or 4;

R³ represents hydrogen or methoxy;

m represents 1 or 2;

R⁴ represents hydrogen, amino or C₁₋₃ alkylcarbonylamino; and

R⁵ represents hydrogen or halo.

The present invention is also concerned with the use of the compounds offormula (I), the pharmaceutically acceptable acid addition salts and thestereochemically isomeric forms thereof for the manufacture of amedicament for treating 5-HT₃ mediated disorders such as anxiety,psychosis, depression, schizophrenia, cognitive disorders, drug abuse,migraine, emesis, irritable bowel syndrome and related disorders.

In the foregoing definitions and hereinafter the term halo definesfluoro, chloro, bromo and iodo, preferably chloro; C₁₋₄ alkyl definesstraight and branch chained saturated hydrocarbon radicals having from 1to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl, preferably methyl.C₁₋₆ alkyl defines C₁₋₄ alkyl and the higher homologues thereof such as,for example, pentyl and hexyl. C₁₋₃ alkylcarbonyl defines straight andbranch chained acyl radicals such as methylcarbonyl, ethylcarbonyl,propylcarbonyl, preferably methylcarbonyl.

The term pharmaceutically acceptable acid addition salt as usedhereinbefore defines the non-toxic, therapeutically active acid additionsalt forms which the compounds of formula (I) may form. The compounds offormula (I), having basic properties, may be converted into thecorresponding therapeutically active, non-toxic acid addition salt formsby treating the free base form with a suitable amount of an appropriateacid following conventional procedures. Examples of appropriate acidsare inorganic acids, for example, hydrohalic acid, e.g. hydrochloric,hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, cyclohexane-sulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. The termpharmaceutically acceptable addition salts also comprises the solvateswhich the compounds of formula (I) may form such as alcoholates and inparticular hydrates.

The compounds of formula (I) may also exist in their tautomeric form.Said form although not explicitly indicated hereinabove is intended tobe included within the scope of the present invention.

The term stereochemically isomeric forms as used hereinbefore definesthe different isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers, and/or enantiomers of the basic moleular structure. Allstereochemically isomeric forms of the compounds of formula (I) both inpure form or in admixture with each other are intended to be embracedwithin the scope of the present invention.

Hereinafter the term `enantiomerically pure` concerns compounds havingan enantiomeric excess of at least 94% (i.e. minimum 97% of oneenantiomer and maximum 3% of the other enantiomer) up to an enantiomericexcess of 100% (i.e. 100% of one enantiomer and none of the other), inparticular compounds having an enantiomeric excess of 96% up to 100%more in particular having an enantiomeric excess of 98% up to 100%. Theterm "enantiomerically enriched" concerns compounds having anenantiomeric excess ranging from more than 0% up to about 94%. The terms"diastereomerically enriched" and "diastereomerically pure" as usedhereinafter should be understood in a similar way, but then havingregard to the diastereomeric excess of the mixture in question.

Interesting compounds for use as 5-HT₃ antagonists are those compoundsof formula (I) wherein R⁵ is halo, preferably chloro.

Also interesting compounds for use as 5-HT₃ antagonists are thosecompounds of formula (I) wherein R⁴ represents hydrogen or amino.

More interesting compounds for use as 5-HT₃ antagonists are thosecompounds of formula (I) wherein

R¹ and R² represent hydrogen;

n represents 2 or 3;

R³ represents methoxy and has the cis-configuration;

m represents 1;

R⁴ represents amino; and

R⁵ represents halo.

Particularly interesting compounds for use as 5-HT₃ antagonists arethose interesting compounds of formula (I), wherein R³ is methoxy havingthe cis-configuration, that are laevo-rotatory.

Preferred compounds are (-)-cis-4-amino-5-chloro-2,3-dihydro-N- 1- 3-(3,4-dihydro-4-oxo-2-pyrimidinyl)amino!propyl!-3-methoxy-4-piperidinyl!-2,2-di-methyl-7-benzofurancarboxamideand (-)-cis-4-amino-5-chloro-N- 1- 2-(3,4-dihydro-4-oxo-2-pyrimidinyl)amino!ethyl!-2,3-dihydro-3-methoxy-4-piperidinyl!-2,2-dimethyl-7-benzofurancarboxamide,and the pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I), wherein R³ is methoxy and has thecis-configuration are represented by formula (I-a). Hereinafter theintermediates wherein R³ is methoxy and where possible has thecis-configuration will be designated by appending the suffix -a to theirnumerical reference.

An additional feature of the present invention comprises the fact thatthe laevo-rotatory enantiomers of the compounds of formula (I) whereinR³ represents methoxy and has the cis-configuration, i.e. thelaevorotatory enantiomers of the compounds of formula (I-a), are deemednovel.

The compounds of formula (I) can generally be prepared followingart-known procedures such as described in EP-0,389,037 and alternativeprocesses known in the art. Some intermediates of formula (II), (III),(IV), (V), (VI), (VII), (IX), (X) and (XIII) are described inEP-0,389,037, EP-0,445,862 and EP-0,076,350. Some methods for preparingcompounds of formula (I), especially compounds of formula (I-a), andnovel intermediates will be described hereinunder.

In the following preparations, the reaction products may be isolatedfrom the reaction mixture and, if necessary, further purified accordingto methodologies generally known in the art such as, for example,extraction, distillation, crystallization, trituration andchromatography.

In order to simplify the structural representations of the compounds offormula (1) and certain starting materials and intermediates thereof,the radical ##STR3## will hereafter be represented by the symbol D andthe radical ##STR4## will hereafter be represented by L.

The compounds of formula (I) may be prepared by N-alkylating apiperidine of formula (II) with an intermediate of formula (III).##STR5##

W¹ as described in the reaction of (III) with (II) and in the followingreaction schemes is an appropriate leaving group such as, for example,halo, e.g. chloro, bromo or iodo, or a sulfonyloxy group, e.g.methanesulfonyloxy, 4-methylbenzenesulfonyloxy and the like leavinggroups. The N-alkylation reaction of (II) with (III) is convenientlyconducted following art-known alkylation procedures.

The compounds of formula (I) may also be prepared by the N-acylation ofan amine of formula (IV) with a carboxylic acid of formula (V) or afunctional derivative thereof, such as an acylhalide, a symmetrical ormixed anhydride or an ester, preferably an activated ester, followingart-known procedures. ##STR6## It may be expedient to protect amino orhydroxy groups during the course of the reaction to avoid undesired sidereactions. Suitable protecting groups comprise readily removable groupssuch as C₁₋₄ alkylcarbonyl, C₁₋₄ alkyloxycarbonyl, phenylmethyl,tertiary butyl and the like protective groups.

The compounds of formula (I) may also be prepared by N-alkylating anintermediate of formula (VII) with an alkylating reagent of formula(VI), wherein R⁶ is hydrogen or C₁₋₆ alkyl and W² is an appropriateleaving group such as, for example, halo, e.g. chloro, bromo or iodo; asulfonyloxy group, e.g. methanesulfonyloxy, 4-methyl-benzenesulfonyloxy;C₁₋₆ alkyloxy, e.g. methoxy, ethoxy; C₁₋₆ alkylthio, e.g. methylthio,ethylthio. When R⁶ is C₁₋₆ alkyl an intermediate of formula (VIII) isformed, which may subsequently be transformed into the final compoundsby cleaving the protective etherfunction. Said cleavage may be carriedout by treating the intermediate of formula (VIII) with an acid, suchas, for example, a hydrohalic acid, e.g. hydrochloric acid. ##STR7## Thecompounds of formula (I) can alternatively be prepared by N-alkylatingan 2-amino-pyridine of formula (IX) with an intermediate of formula (X).##STR8##

The alkylation reactions of (VI) with (VII) and (IX) with (X) may becarried out according to art-known procedures, e.g. by stirring andoptionally heating the reactants without solvent or in admixture with aninert organic solvent such as, for example an alcohol, e.g. 2-propanol,butanol, a dipolar aprotic solvent, e.g. acetonitrile optionally in thepresence of an appropriate base, e.g. potassium carbonate.

The compounds of formula (I) may also be converted into each otherfollowing art-known group-transformation reactions.

Aminogroups may be transformed in C₁₋₃ alkylcarbonylamino by art-knownN-acylation reactions and conversely C₁₋₃ alkylcarbonylamino groups maybe transformed in amino groups using art-known hydrolysis reactions.

Compounds of formula (I), wherein R⁵ is hydrogen may be transformed inthe corresponding compounds wherein R⁵ is halogen, using art-knownhalogenation techniques.

The intermediates of formula (VII) may be prepared by N-alkylating anintermediate of formula (II) with a reagent of formula (XI) andsubsequently removing the protective group P in the thus obtainedintermediate (XIII) following art-known reaction procedures. ##STR9##

In (XI), (XIII) and the other intermediates containing the group P inthe following schemes, P represents a suitable protective group which isreadily removable by, for example, hydrogenolysis or hydrolysis.Preferred protective groups are, for example, C₁₋₄ alkylcarbonyl, e.g.methylcarbonyl, ethylcarbonyl; C₁₋₄ alkoxycarbonyl, e.g. ethoxycarbonyl,1,1'-dimethylethyloxycarbonyl; trihalomethylcarbonyl, e.g.trifluoro-methylcarbonyl; diphenylmethyl; triphenylmethyl or arylmethyl,wherein aryl is phenyl optionally substituted with up to twosubstituents selected from C₁₋₄ alkyloxy or halo.

The intermediates of formula (II) may be derived from an appropriatelysubstituted piperidine of formula (XIV) with an intermediate acid offormula (V) or a functional derivative thereof, following art-knownamide forming procedures, and subsequently removing the protective groupP¹, following art-known procedures. P¹ represents a readily removableprotective group and has the same meaning as the group P hereinabove.##STR10## The intermediates of formula (XIV), wherein R³ is methoxy andhas the cis-configuration, i.e. the 3-methoxy-4-aminopiperidines offormula (XIV-a), may be obtained, for example, by catalytichydrogenation of an imine of formula (XVI-a) and subsequentlytransforming the secondary amine of formula (XV-a) into the3-methoxy-4-aminopiperidines of formula (XIV-a) by hydrogenolysis. Theimines of formula (XVI-a) may be prepared following art-known imineformation procedures starting from a 3-methoxy-4-oxo-piperidine offormula (XVII-a) and an amine of formula (XVIII). ##STR11##

In the intermediates of formula (XVIII), (XVI-a) and (XV-a), R⁷ ishydrogen, C₁₋₆ alkyl or hydroxyC₁₋₆ alkyl and Ar is phenyl optionallysubstituted with halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy; or naphthyl optionallysubstituted with halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy.

The reactionsequence starting from an intermediate of formula (XVII-a)up to an intermediate of formula (XIV-a) may also be performed as aone-pot procedure.

Enantiomerically enriched or enantiomerically pure intermediates offormula (XV-a) and (XIV-a) may be prepared according to one of thefollowing methods.

The starting racemic 3-methoxy-4-oxo-piperidine of formula (XVII-a) orthe corresponding ketal such as, for example, a diC₁₋₆ alkylketal, e.g.4,4-diethoxy-3-methoxypiperidine, may be separated into its enantiomersand further converted into an enantiomerically purecis-3-methoxy-4-aminopiperidine of formula (XIV-a) as describedhereinabove. Said separation in enantiomers can be performed, forinstance, by column chromatography using a chiral stationary phase, e.g.Chiracell OD.

Alternatively, the intermediate imine of formula (XVI-a) can be preparedusing one of the enantiomers of a chiral amine of formula (XVIII),wherein R⁷ is defined as hereinabove but other than hydrogen, saidamines being represented by (XVIII-b), e.g.(-)-(R)-α-aminobenzene-ethanol or (+)-S-α-aminobenzeneethanol, whichafter hydrogenation yields diastereomeric amines of formula (XV-a),which may be conveniently separated by physical separation methods suchas selective crystallization or chromatographic techniques.Hydrogenolysis of the arylmethylgroup (Ar--CH(R⁷)-) from the respectivediastereomeric amines of formula (XV-a) yields the respectiveenantiomeric 3-methoxy-4-aminopiperidines of formula (XIV-a).

Yet another way of obtaining enantiomerically pure3-methoxy-4-aminopiperidines of formula (XIV-a) was found during theoptimization of the above reaction sequence. When one reacts a racemicketone such as a 3-methoxy-4-oxo-piperidine of formula (XVII-a) with anenantiomerically pure chiral amine of formula (XVIII-b), e.g.(-)-(S)-α-methylbenzylamine, and subsequently hydrogenates the thusformed imine of formula (XVI-a), one would expect a ratio ofdiastereomeric amines of formula (XV-a) of approximately 1:1 .Unexpectedly, however, it was found that after the above reactionsequence said diastereomeric ratio differs substantially from the ratio1:1. In other words, the amines of formula (XV-a) werediastereomerically enriched or even diastereomerically pure. Hence, inthe course of this reaction sequence one diastereomer is converted intothe other by configurational inversion of the stereocenter bearing themethoxygroup.

Thus, a novel and inventive way to obtain novel enantiomericallyenriched or enantiomerically pure 3-methoxy-4-aminopiperidines offormula (XIV-a) and more in general intermediates of formula (XIX-a) wasfound following the procedure described in more detail hereinunder.##STR12##

In (XIX-a), (XX-a), (XXI-a) and (XXII-a) the radical A representshydrogen, --(CH₂)_(n) --NH₂, --(CH₂)_(n) --NH--P, P¹ or L, wherein n, P,P¹ and L are as defined hereinabove. A racemic mixture of3-methoxy-4-oxo-piperidine of formula (XXII-a) may be reacted with oneenantiomer of a chiral amine of formula (XXIII), wherein R⁸ is C₁₋₆alkyl or hydroxyC₁₋₆ alkyl, Ar is phenyl optionally substituted withhalo, C₁₋₆ alkyl, C₁₋₆ alkyloxy; or naphtyl optionally substituted withhalo, C₁₋₆ alkyl, C₁₋₆ alkyloxy; yielding a diastereomeric mixture ofthe intermediate imine of formula (XXI-a). Said reaction may be carriedout using art-known imine-formation procedures, such as, for instance,stirring the reactants at reflux temperature in a reaction-inert solventsuch as, for example, an aromatic hydrocarbon, e.g. methylbenzene, usinga Dean-Stark apparatus.

The imine of formula (XXI-a) may be isolated and, if necessary,purified, for instance by column chromatography, distillation orcystallization. Subsequently the imine may be hydrogenated by stirringthe imine under hydrogen atmosphere in a suitable solvent such as, forexample, an alcohol, e.g. methanol or ethanol; an ether, e.g.tetrahydrofuran or 2,2'-oxybispropane; an ester, e.g. ethylacetate; anaromatic hydrocarbon, e.g. methylbenzene; in the presence of appropriatecatalysts, e.g. palladium-on-charcoal, platinum-on-charcoal, rhodium-oncarbon and the like, yielding a diastereomerically enriched ordiastereochemically pure amine of formula (XX-a).

Alternatively, the intermediate imine of formula (XXI-a) is notisolated. In this case a racemic mixture of a 3-methoxy-4-oxo-piperidineof formula (XXII-a) is reacted with one of the enantiomers of a chiralamine of formula (XXIII) under hydrogenation conditions, yieldingdiastereomerically enriched or diastereomerically pure intermediateamines of formula (XX-a). Said reaction is performed in analogousreaction conditions as described hereinabove. However in this case, thereaction preferably is performed in admixture with an acid, such as,acetic acid, oxalic acid, chloroacetic acid,2-hydroxy-1,2,3-propanetricarboxylic acid, and in particular (-)S-(R*,R*)!-2,3-dihydroxy-butanedioic acid, especially when the solventis an alcohol.

In the amines of formula (XXIII), R⁸ is suitably hydroxymethyl, methylor ethyl, especially methyl and Ar is preferably an unsubstituted phenylor naphthyl, especially phenyl. Preferred amines of formula (XXIII) arethe enantiomers of α-methylbenzyl-amine, i.e.(-)-(S)-α-methylbenzylamine or (+)-(R)-(α-methylbenzylamine.

Sometimes, during the hydrogenation reaction a small amount oftrans-3-methoxy-4-aminoderivative can be formed, which may be removed bycrystallization or chromatography.

A preferred way of preparing a diastereomerically enriched or pure amineof formula (XX-a) is first preparing an imine of formula (XXI-a) withone enantiomer of α-methyl-benzylamine and subsequently hydrogenatingthe imine of formula (XXI-a) by stirring it in methylbenzene under ahydrogen atmosphere using a rhodium catalyst.

In order to avoid the undesired further hydrogenation of certainfunctional groups in the reactants and the reaction products, it may beadvantageous to add an appropriate catalyst-poison to the reactionmixture, e.g. thiophene, quinoline-sulphur and the like. Higherpressures and/or temperatures may enhance the reaction rate.

The resulting intermediate of formula (XX-a) has a diastereomeric ratio,that differs very much from the 1:1 ratio. In other words, theintermediate of formula (XX-a) is diastereomerically enriched ordiastereomerically pure. The respective diastereomeric forms may then,if necessary, be further separated using conventional physical methodssuch as chromatography or fractional crystallization optionally aftersalt formation. The thus obtained diastereomerically pure amines offormula (XX-a) may then be further hydrogenolyzed, removing the chiralauxiliary group Ar--CH(R⁸)--, yielding enantiomerically pure3-methoxy-4-aminopiperidines of formula (XIX-a).

It is noteworthy that the configuration of the stereocenter bearing themethoxygroup is determined by the configuration of the enantiomericallypure amine of formula (XVIII) that is used. Hence, either configurationof said stereocenter can be obtained by selection of one or the otherenantiomer of the amine of formula (XXIII). It may further be noted thatthe choice of the acid used during the hydrogenation of the imine, canalso influence up to a certain degree the diastereomeric ratio of theamines of formula (XIX-a). The choice of catalyst can also influence upto a certain degree the amount of trans-4-amino-3-methoxy derivativethat is formed.

The diastereomerically enriched or diastereomerically pure intermediatesof formula (XX-a) and the enantiomerically enriched or enantiomericallypure intermediates of formula (XIX-a) and the pharmaceuticallyacceptable acid addition salts thereof are deemed novel. Also theenantiomerically enriched or enantiomerically pure intermediates offormula (II-a), (IV-a), (VII-a), (X-a), (XIII-a), (XIV-a) and thepharmaceutically acceptable acid addition salts are also deemed novel.Said intermediates may be prepared as described hereinabove startingfrom enantiomerically enriched or enantiomerically pure intermediates offormula (XIV-a).

In this way and starting from enantiomerically enriched orenantiomerically pure intermediates described hereinabove a novel andinventive way to prepare enantiomerically enriched or enantiomericallypure compounds of formula (I-a), especially, the laevo-rotatoryenantiomers of the compounds of formula (I-a) is provided.

It is evident that the cis and trans diastereomeric racemates of thecompounds of formula (I), (I-a), or any of the other intermediates mayalso be resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of art-known methodologies.Diastereoisomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g. countercurrent distribution, and enantiomers may be separated from each otherby the selective crystallization of their diastereomeric salts withenantiomerically pure acids or their enantiomerically pure derivatives.

The compounds of formula (I), the pharmaceutically acceptable salts andstereoisomeric forms are 5-HT₃ -receptor antagonists, as demonstrated bythe fact that they have been found active, for example, in antagonisingthe von Bezold-Jarish chemoreflex evoked by serotonin in rats(Pharmacology and Toxicology, 70, Supp II, 17-22 (1992)). This test isdescribed hereinafter as example 10.

The compounds of formula (I), especially the compounds of formula (I-a),are active during a long period of time. Moreover, the present compoundsof formula (I), especially the compounds of formula (I-a), show a highdegree of cardiovascular safety.

In view of their 5-HT₃ -antagonistic activity the subject compounds maybe formulated into various pharmaceutical forms for administrationpurposes. To prepare these pharmaceutical compositions, an effectiveamount of a particular compound, in base or acid addition salt form, asthe active ingredient is intimately mixed with a pharmaceuticallyacceptable carrier. Said carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thesepharmaceutical compositions are desirably in unitary dosage formsuitable, preferably, for administration orally, rectally or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wetting agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause asignificant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of the compounds of formula(I) due to their increased water solubility over the corresponding baseform, are obviously more suitable in the preparation of aqueouscompositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

In view of their 5-HT₃ -antagonising activity the compounds of formula(I) and especially the novel compounds of formula (I-a) are useful inthe treatment of 5-HT₃ -mediated disorders such as anxiety, psychosis,depression (Arzneim. Forsch., 42(1), 239-246 (1992)), schizophrenia,cognitive disorders, e.g. memory impairment (Arzneim. Forsch., 42(1),246-249 (1992)), drug abuse, migraine, emesis, e.g. cytotoxic drug andradiation induced emesis (Drugs 42(4), 551-568 (1991)), irritable bowelsyndrome, especially diarrheapredominant irritable bowel syndrome, andrelated disorders. Consequently, the present invention provides a methodof treating warm-blooded animals suffering from 5-HT₃ -mediated diseasessuch as anxiety, psychosis, depression, schizophrenia, cognitivedisorders, e.g. memory impairment, drug abuse, migraine, emesis, e.g.cytotoxic drug and radiation induced emesis, irritable bowel syndrome,especially diarrheapredominant irritable bowel syndrome, and relateddisorders. Said method comprises the systemic administration of aneffective 5-HT₃ -antagonistic amount of a compound of formula (I), apharmaceutically acceptable acid addition salt or a stereoisomeric formthereof, to warm-blooded animals.

The present compounds of formula (I) are useful for the manufacture of amedicament for treating 5-HT₃ mediated diseases. The novel compounds offormula (I-a) are useful as a medicine.

In general it is contemplated that an effective amount would be fromabout 0.001 mg/kg to about 50 mg/kg body weight, preferably from about0.02 mg/kg to about 5 mg/kg body weight. A method of treatment may alsoinclude administering the active ingredient on a regimen of between twoor four intakes per day.

EXPERIMENTAL PART

A. Preparation of the intermediates

EXAMPLE 1

a) 3,4,4-trimethoxy-1-(phenylmethyl)piperidine (0.676 mol) was purifiedby column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 98/2).The pure fractions were collected and the solvent was evaporated. Thisresidue (mixture of enantiomers) was separated in it's enantiomers bycolumn chromatography over a Chiracell OD column (eluent:hexanes/2-propanol 98.5/1.5). The fraction, corresponding to a firstchromatographic peak, was collected and the solvent was evaporated. Asample was purified by distillation (bp at 0.5 mmHg: 120° C.), yielding:56 g of (-)-3,4,4-trimethoxy-1-(phenylmethyl)piperidine α!₂₀ ^(D)=-54.00° (c=0.5% in methanol) (interm. 1).

The fraction, corresponding to a second chromatographic peak, wascollected and the solvent was evaporated. A sample was purified bydistillation (bp at 0.5 mmHg: 120° C.), yielding 64 g of(+)-3,4,4-trimethoxy-1-(phenylmethyl)piperidine; α!₂₀ ^(D) =49.60°(c=0.5% in methanol) (interm. 2).

b) A mixture of intermediate (1) (0.21 mol) in methanol (600 ml) washydrogenated at 50° C. with palladium-on-charcoal 10% (3g) as acatalyst. After uptake of H₂ (1 equiv), the catalyst was filtered off.Calcium oxide (0.63 mol) was added to the filtrate. The reaction mixturewas stirred at room temperature. Ethyl chloroformate (0.63 mol) wasadded dropwise. The reaction mixture was stirred for 2 hours at 50° C.The reaction mixture was stirred overnight at room temperature. Thesolvent was evaporated. Methylbenzene was added to the residue. Thesuspension was filtered and the filtrate was evaporated. The residue waspurified by distillation, yielding 32.6 g (63%) of (-)-ethyl3,4,4-trimethoxy-1-piperidinecarboxylate; α!₂₀ ^(D) =-39.40° (c=0.5% inmethanol) (interm. 3).

c) A mixture of interm. (3) (0.132 mol), 4-methylbenzenesulfonic acid(0.6 g) in 2-propanone (180 ml) and water (30 ml) was stirred andrefluxed for 18 hours. The reaction mixture was cooled andN,N-diethylethanamine (0.6 ml) was added. The solvent was evaporated(temperature was kept <40° C.). The residue was dissolved in CH₂ Cl₂.This solution was washed twice with a saturated NaCl solution. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by distillation, yielding 19.2 g(-)-ethyl 3-methoxy-4-oxo-1-piperidine-carboxylate (72.3%); α!₂₀ ^(D)=44.40° (c=0.5% in methanol) (interm. 4).

d) A mixture of intermediate (4) (0.095 mol) and benzenemethanamine(0.11 mol) in methanol (200 ml) was hydrogenated under atmosphericconditions with palladium on activated charcoal 10% (2 g) as a catalystin the presence of 4% solution of thiophene in 2,2'-oxybispropane (2ml). After uptake of hydrogen, the catalyst was filtered off and thefiltrate was evaporated. The residue was dissolved in methanol (250 ml)and the resulting mixture was hydrogenated at 50° C. with palladium onactivated charcoal 10% (2 g) as a catalyst. After uptake of hydrogen (1equiv), the catalyst was filtered off and the filtrate was evaporated.The residue was purified by distillation (bp at 0.1 mm Hg: 85° C.),yielding 13.4 g (70%) ethyl(-)-cis-4-amino-3-methoxy-1-piperidinecarboxylate; α!₂₀ ^(D) =78.9°(c=1% in methanol) (interm. 5).

In a similar manner but starting from intermediate (2) was alsoprepared: (+)-ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate; α!₂₀^(D) =80.64° (c=0.6% in methanol) (interm. 6).

EXAMPLE 2

a) A mixture of ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate (0.5 mol),(-)-(S)-α-methylbenzenemethanamine (0.53 mol), 4-methylbenzenesulfonicacid monohydrate (1.25 g) and methylbenzene (625 ml) was stirred andrefluxed with a Dean-Stark apparatus for 3 hours. The reaction mixturewas evaporated and distilled, yielding 121 g (79.5%) of (-)-ethylcis(S)!-3-methoxy-4- (1-phenylethyl)imino!-1-piperidine-carboxylate(interm. 7).

b) A mixture of intermediate (7) (0.4 mol) and methylbenzene (750 ml)was hydrogenated at room temperature and atmospheric pressure withrhodium-on-carbon (5 g) as a catalyst. After uptake of hydrogen (1 eq.),the catalyst was filtered off and the filtrate was evaporated. Theresidue was dissolved in 4-methyl-2-pentanone and converted into the4-methylbenzenesulfonic acid salt (1:1) with 4-methylbenzenesulfonicacid. monohydrate (1 eq.). The salt was filtered off and dried. Thisfraction was recrystallized twice from a mixture of2,2'-oxybispropane/methanol (250 ml/180 ml). The precipitated productwas filtered off and dried, yielding 61.7 g (32.5%) of (-)-ethylcis(S)!-3-methoxy-4- (1-phenylethyl)amino!-1-piperidinecarboxylate4-methylbenzene-sulfonate (1:1); α!₂₀ ^(D) =-62.16° (c=1% in methanol)(interm. 8).

In a similar manner, but using (+)-(R)-α-methylbenzene methanamine wasprepared: (+)-ethyl cis, (R)!-3-methoxy-4-(1-phenylethyl)amino!-1-piperidinecarboxylate 4-methylbenzenesulfonate(1:1); α!₂₀ ^(D) =62.79° (c=1% in methanol) (interm. 9).

EXAMPLE 3

a) A mixture of ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate (0.2 mol),(-)-(S)-α-methylbenzenemethanamine (0.4 mol) and (-)-S-(R*,R*)!2,3-dihydroxybutanedioic acid (0.2 mol) in methanol (500 ml)was hydrogenated at room temperature and atmospheric pressure withpalladium on activated charcoal 10% (2 g) as a catalyst, in the presenceof a 4% solution of thiophene in 2,2'-oxybispropane (2 ml). After uptakeof H₂ (1 eq.), the catalyst was filtered off and the filtrate wasevaporated. The residue was partitioned between methylbenzene and H₂O/NH₄ OH. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated. The residue was dissolved in4-methyl-2-pentanone and converted into the 4-methylbenzenesulfonic acidsalt (1:1) with 4-methylbenzenesulfonic acid. monohydrate (1 eq.). Thesalt was filtered off and dried. This fraction was recrystallized from2,2'-oxybispropane/CH₃ OH (500 ml/100 ml). The mixture was stirred for24 hours. The precipitate was filtered off and dried (vacuum; 50° C.),yielding 32 g of (-)-ethyl cis,(S)!-3-methoxy-4-(1-phenylethyl)amino!-1-piperidinecarboxylate 4-methylbenzenesulfonate(1:1); α!₂₀ ^(D) =-61.6° (c=0.5% in methanol) (interm. 8).

In a similar manner, but using (+)-(R)-α-methylbenzene methanamine, wasalso prepared: (+)-ethyl cis, (R)!-3-methoxy-4-(1-phenylethyl)amino!-1-piperidinecarboxylate 4-methylbenzenesulfonate(1:1) (interm. 9).

b) Intermediate (8) (0.067 mol) was converted into the free base withaqueous ammonia. This mixture was extracted with methylbenzene. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residual free base was dissolved in methanol (250 ml)and hydrogenated at room temperature and atmospheric pressure withpalladium on activated charcoal 10% (2 g) as a catalyst. After uptake ofH₂ (1 equiv), the catalyst was filtered off and the filtrate wasevaporated. The residue was purified by distillation (boiling point at0.1 mm Hg: 85° C.), yielding 9.9 g (79.2%) of ethyl(-)-cis-4-amino-3-methoxy-1-piperidinecarboxylate (interrn. 5). In asimilar manner, but starting from intermediate (9), was also prepared:(+)-ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate (interm. 6).

EXAMPLE 4

a) A mixture of 53.3 g of ethyl 3-methoxy-4-oxo-1-piperidinecarboxylate(described in EP-patent 76.350), 33 g of (-)-(R)-α-aminobenzeneethanoland 700 ml of ethanol was refluxed overnight. After cooling, thereaction mixture was evaporated and the residue was distilled, yielding59.1 g (92%) of ethyl (R)-4-(2-hydroxy-1-phenylethyl)imino!-3-methoxy-1-piperidinecarboxylate; bp.180° C. (pressure=3.75.10⁻⁴ Pa) (interm. 10).

b) A solution of 59.1 g of intermediate (10) in 500 ml of ethanol washydrogenated at normal pressure and at room temperature with 2 g ofplatinum-on-charcoal catalyst. After the calculated amount of hydrogenwas taken up, the catalyst was filtered off and the filtrate wasevaporated. The residue was purified over NH₂ -silicagel (eluent CH₂ Cl₂/cyclohexane/methanol 60:40:0.5). The pure fractions were collected andthe eluent was evaporated, yielding 18 g (30%) of ethyl (-)-4(R),cis!-4-(2-hydroxy-1-phenylethyl)amino!-3-methoxy-1-piperidinecarboxylate as aresidue; α!₂₀ ^(D) =-96.70° (c=0.5% in methanol) (interm. 11).

c) A solution of 18 g of intermediate (11) in 250 ml of methanol washydrogenated at normal pressure and at room temperature with 2 g ofpaladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The resiude was distilled, yielding 6.2 g (55%) of ethyl(-)-cis-4-amino-3-methoxy-1-piperidinecarboxylate (interm. 5).

EXAMPLE 5

a) 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxylic acid(described in EP-0,389,037) (0.05 mol) was dissolved in a mixture ofN,N-diethylethanamine (7 ml) and trichloromethane (250 ml). Ethylcarbonochloridate (0.05 mol) was added dropwise at <10° C. The reactionmixture was stirred for 30 min at <10° C. The mixture was added to asolution of intermediate (5) (0.047 mol) in trichloromethane (250 ml),stirred at 10° C. The reaction mixture was stirred for 30 min at roomtemperature. The reaction mixture was washed with water, 5% NaOH andagain water. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 98/2). The purefractions were collected and the solvent was evaporated, yielding 19 g(94%) of (+)-ethyl cis-4-(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)-carbonylamino!-3-methoxy-1-piperidinecarboxylate(interm. 12).

b) A mixture of intermediate (12) (0.045 mol) and potassium hydroxide(0.45 mol) in 2-propanol (300 ml) was stirred and refluxed for 12 hours.The reaction mixture was cooled and the solvent was evaporated. Water(100 ml) was added to the residue. The solvent was evaporated. Theresidue was partitioned between dichloromethane and water. The organiclayer was separated, washed with water, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 97/3). Thepure fractions were collected and the solvent was evaporated. Theresidue was dried (vacuum;50° C.), yielding: 12.5 g(+)-cis-4-amino-5-chloro-2,3-dihydro-N-(3-methoxy-4-piperidinyl)-2,2-dimethyl-7-benzofurancarboxamide(77.2%); α!₂₀ ³⁶⁵ =33.40° (c=0.5% in methanol) (interm. 13).

EXAMPLE 6

a) A mixture of intermediate (13) (0.017 mol), ethyl(2-chloroethyl)carbamate (0.02 mol) and N,N-diethylethanamine (0.022mol) in N,N-dimethylformamide (150 ml) was stirred for 72 h at 70° C.The reaction mixture was cooled and the solvent was evaporated. Theresidue was partitioned between dichloromethane and water. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified over silica gel on a glass filter(eluent: CH₂ Cl₂ /CH₃ OH 97/3). The pure fractions were collected andthe solvent was evaporated, yielding: 5 g (+)-ethyl cis- 2- 4-(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonyl!-amino!-3-methoxy-1-piperidinyl!ethyl!carbamate(63%); α!₂₀ ^(D) =1.20° (c=0.5% in methanol) (interm. 14).

b) A mixture of intermediate (14) (0.0106 mol) and potassium hydroxide(0.106 mol) in 2-propanol (45 ml) was stirred and refluxed for 4 hours.The mixture was cooled. The solvent was evaporated and the residue wasstirred in water, then evaporated again. The residue was dissolved indichloromethane and this solution was washed with a small volume ofwater, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent: CH₂ Cl₂/CH₃ OH/(CH₃ OH/NH₃) 90/9/1). The pure fractions were collected and thesolvent was evaporated, yielding 3.2 g (76%) (-)-cis-4-amino-N-1-(2-aminoethyl)-3-methoxy-4-piperidinyl!-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide;α!₂₀ ^(D) =-1.50° (c=0.2% in methanol) (interm. 15).

EXAMPLE 7

a) A mixture of intermediate (13) (0.023 mol) and 2-propenenittile(0.028 mol) in 2-propanol (150 ml) was stirred and refluxed for 16hours. The reaction mixture was cooled and the solvent was evaporated,yielding 8 g (85.5%) (-)-cis-4-amino-5-chloro-N-1-(2-cyanoethyl)-3-methoxy-4-piperidinyl!-2,3-dihydro-2,2-dimethyl-7-benzofuran-carboxamide;α!₂₀ ^(D) =1.60° (c=0.5% in methanol) (interm. 16).

b) A mixture of intermediate (16) (0.02 mol) in methanol (250 ml) andtetrahydrofuran (100 ml) was hydrogenated under atmospheric conditionswith Raney nickel (3 g) as a catalyst. After uptake of hydrogen (2equiv), the catalyst was filtered off and the filtrate was evaporated,yielding 7 g (85.2%) (-)-cis-4-amino-N-1-(3-aminopropyl)-3-methoxy4-piperidinyl!-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamideinterm. 17).

EXAMPLE 8

a) Intermediate (17) (0.769 mol) was dissolved in 1-butanol (2310 ml)(heating to 50° C. required). Potassium carbonate (1.538 mol) was addedat 30° C. (heterogeneous). 2-Chloro-4-methoxypyrimidine (0.960 mol) wasadded and the reaction mixture was heated to reflux temperature (104°C.). The reaction mixture was stirred and refluxed for 11 hours. Themixture was allowed to cool to 20° C. Water (769 ml) was added and themixture was stirred for 15 minutes. The layers were separated. Theorganic layer was evaporated (1.66 mm Hg; 60° C.), yielding 458.9 g(92.1%) of (±)-cis-4-amino-5-chloro-2,3-dihydro-N- 3-methoxy-1- 3-(4-methoxy-2-pyrimidinyl)amino!propyl!-4-piperidinyl!-2,2-dimethyl-7-benzofurancarboxamide(interm. 18).

b) Hydrochloric acid in 2-propanol (434 ml) was added dropwise over a15-minutes period to a solution of intermediate (18) (0.769 mol) in4-methyl-2-pentanone (3845 ml), stirred at 15°-20° C. (cooling on icebath was required). The reaction mixture was stirred for 1 hour at 15°C. The precipitate was filtered off, washed with 4-methyl-2-pentanone(769 ml) and dried (vacuum; 50° C.), yielding 425.9 g (93.6%) of(±)-cis-4-amino-5-chloro-2,3-dihydro-N- 3-methoxy-1- 3-(4-methoxy-2-pyrimidinyl)amino!-propyl!-4piperidinyl!-2,2-dimethyl-7-benzofurancarboxamidedihydrochloride (interm. 19)

B. Preparation of the final compounds

EXAMPLE 9

A mixture of intermediate (17) (0.017 mol) and2-methylthio-4-pyrimidinone (0.022 mol) in acetonitrile (300 ml) wasstirred and refluxed for 16 hours. Extra 2-methylthio-4-pyrimidinone (2g) was added and the reaction mixture was stirred and refluxed for 16hours. The reaction mixture was cooled. The solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent: CH₂ Cl₂/CH₃ OH/(CH₃ OH/NH₃) 90/9/1). The pure fractions were collected and thesolvent was evaporated. The residue was triturated in2,2'-oxybispropane. The solid was filtered off and dried (vacuum; roomtemperature), yielding 2.65 g (29.7%)(-)-cis-4-amino-5-chloro-2,3-dihydro-N- 1- 3-(3,4-dihydro-4-oxo-2-pyrimidinyl)amino!propyl!-3-methoxy-4-piperidinyl!-2,2-dimethyl-7-benzofurancarboxamide;mp. 164.3° C.; α!₂₀ ^(D) =-17.54° (c=1% in methanol) (comp. 1).

In this manner there were prepared:

                  TABLE 1    ______________________________________     ##STR13##    Co. No.          R.sup.3 R.sup.4                         n   m   physical data    ______________________________________     1    OCH.sub.3                  NH.sub.2                         3   1   cis; mp. 164.3° C.;                                  α!.sub.20.sup.D = -17.54°                                 (c = 1% in methanol)     2    OCH.sub.3                  NH.sub.2                         2   1   cis; mp. 179.9° C.,                                  α!.sub.20.sup.365 =                                 -156.45° (c = 0.1% in CH.sub.3 OH)     3    OCH.sub.3                  NH.sub.2                         3   1   cis; mp. 164.3° C.,                                  α!.sub.20.sup.D = 17.21°                                 (c = 1% in CH.sub.3 OH)     4    OCH.sub.3                  NH.sub.2                         2   1   cis;  α!.sub.20.sup.365                                 = 158.53° (c = 0.1% in                                 CH.sub.3 OH)     5    OCH.sub.3                  NH.sub.2                         3   1   cis; 2.5 H.sub.2 O/mp. 163.8° C.     6    OCH.sub.3                  NH.sub.2                         2   1   cis; mp. 198.8° C.     7    H       NH.sub.2                         2   1   mp. 204.4° C.     8    H       NH.sub.2                         3   1   H.sub.2 O/mp. 165.8° C.     9    H       NH.sub.2                         3   2   mp. 221.1° C.    10    H       H      2   1   mp. 126.9° C.    11    H       H      3   2   mp. 106.1° C.    ______________________________________

EXAMPLE 10

A mixture of 4.15 g of 2-chloro-4-hydroxyquinazoline, 4.57 g of4-amino-N-1-(3-aminopropyl)-4-piperidinyl!-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide(described in EP-0, 445, 862) and 0.80 g of calcium oxide was stirredfor 1 hour at 140° C. The reaction mixture was dissolved in a mixture ofdichloromethane and methanol. The whole was washed with water, dried,filtered and evaporated. The residue was purified twice by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 90:10; CH₂ Cl₂ /CH₃OH(NH₃) 88:12 ). The eluent of the desired on was evaporated and theresidue was boiled in 2,2'-oxybispropane. The product was filtered offand dried, yielding 3.2 g (50.8%) of 4-amino-5-chloro-2,3-dihydro-N- 1-3-(4-hydroxy-2-quinazolinyl)amino!propyl!-4-piperidinyl!-2,2-dimethyl-7-benzofurancarboxamide;mp. 159.6° C. (comp. 12).

In this manner there were prepared:

                                      TABLE 2    __________________________________________________________________________     ##STR14##    Co. No.          R.sup.3               R.sup.4   n  physical data    __________________________________________________________________________    12    H    NH.sub.2  3  mp. 159.6° C.    13    H    NH.sub.2  4  mp. 152.3° C.    14    H    NH.sub.2  2  mp. 160° C. (decomp.)    15    OCH.sub.3               NH.sub.2  3  cis/1/2 H.sub.2 O/mp. 185.6° C.    16    OCH.sub.3               NHCOCH.sub.3                         3  cis; H.sub.2 O/mp. 181.2° C.    17    OCH.sub.3               H         3  cis; mp. 140.5° C.    18    OCH.sub.3               H         2  cis; mp. 150.0° C.    19    H    H         2  mp. 238.1° C.    20    H    H         3  mp. 131.1° C.    __________________________________________________________________________

EXAMPLE 11

A mixture of 2.6 g of 2,6-dichloro-4-quinazolinol (described inJ.Med.Chem., 1968, p.130), 3.7 g of 4-amino-N-1-(2-aminoethyl)-4-piperidinyl!-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide(described in EP-0, 445, 862), 0.8 g of calcium oxide and 5.64 g ofN,N-dimethylacetamide was stirred for 3 hours at 140° C. After cooling,the reaction mixture was evaporated and the residue was taken up in amixture of dichloromethane and methanol. The whole was washed withwater. The partly precipitated product was filtered off (firstfraction). The organic layer was decanted, dried, filtered andevaporated (second fraction). The combined fractions were purified twiceby column chromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 95:5; CH₂ Cl₂/CH₃ OH 92:8). The eluent of the desired fraction was evaporated and theresidue was crystallized from acetonitrile. At 0° C., the product wasfiltered off and dried in vacuo at 60° C., yielding 1 g (18.3%) of4-amino-5-chloro-N- 1- 2-(6-chloro-4-hydroxy-2-quinazolinyl)amino!ethyl!-4-piperidinyl!-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide;mp. 206.6° C. (comp. 21).

In this manner there were prepared:

                                      TABLE 3    __________________________________________________________________________     ##STR15##    Co. No.         R.sup.1, R.sup.2                      R.sup.3                          n  physical data    __________________________________________________________________________    21   CHCHC(Cl)CH  H   2  mp. 206.6° C.    22   CHC(Cl)CHCH  H   2  mp. 242.4° C.    23   CHC(Cl)CHCH  OCH.sub.3                          3  mp. 215.5° C.; cis    24   CHCHC(Cl)CH  OCH.sub.3                          3  1/2 H.sub.2 O/mp. 237.9° C.;    __________________________________________________________________________                             cis

EXAMPLE 12

Water (2880 ml) was added to intermediate (19) (0.72 mol, resulting incomplete dissolution of intermediate (19). Hydrochloric acid (193 ml)was added dropwise. The reaction mixture was heated to refluxtemperature (95° C). The reaction mixture was stirred and refluxed for24 hours. More hydrochloric acid (128.6 ml) was added at refluxtemperature. The reaction mixture was stirred and refluxed for 2.5hours. Heating was stopped. Dichloromethane (360 ml) was added. Thelayers were separated. Dichloromethane (1080 ml) was added to theaqueous phase. At 20°-25° C., the biphasic mixture was alkalized withammonium hydroxide (433 ml) (until pH>10; addition over a 30-minutesperiod; external cooling required|; the mixture was homogeneous atstart, precipitation resulted at pH=6-7 and dissolved at higher pH). Thelayers were separated. The aqueous layer was extracted withdichloromethane (360 ml). The organic extracts were combined, dried,filtered and evaporated (vacuum; 40° C.). The residue was dried (vacuum;40° C.), yielding 321.2 g (88.3%) of (-)-cis-4-amino-5-chloro-N- 1- 3-(3,4-dihydro-4-oxo-2-pyrimidinyl)amino!propyl!-3-methoxy-4-piperidinyl!-2,3-dihydro-2,2-dimethyl-7-benzofurancarboxamide(comp. 1).

C. Pharmacological example

EXAMPLE 13

von Bezold Jarish test

Male spontaneous hypertensive rats (±6 months) were anaesthetized byether inhalation and the femoral vein and artery were dissected andcannulated with polyethylene catheters. Lidocaine (20%) was administeredto the wound around the cannulas to induce local analgesia.

The animals were restrained in Bollman cages, and the arterial catheterwas connected to a strain guage blood pressure transducer and systolicpressure was analysed. When the animals were fully awake a controlinjection of serotonin (0.04 mg/kg) was given via the femoral veincatheter. The response of the systolic blood pressure to a intravenousserotine injection normally evolves in three phases: 1) a short andsharp decrease (von Bezold-Jarish reflex), 2) an increase and 3) alonger lasting decrease in systolic blood pressure. Inhibition of thefirst sharp decrease in blood pressure (von Bezold-Jarish reflex) istaken as a measure for 5-HT₃ -antagonism. Some time after the controlinjection of serotonin the test compound was injected intraperitoneally.After 30 minutes serotonin was again injected intravenously and thepresence or absence of the first short and sharp decrease was recorded.The same procedure was repeated after 60 minutes. The compounds weretested at different doses.

The Lowest Active Dose (LAD) which is shown in Table 4 may be defined asthe dose (in mg/kg body weight) at which at least half of the animalstested show inhibition of the von Bezold-Jarish reflex.

                  TABLE 4    ______________________________________           Co. No.                 LAD (mg/kg)    ______________________________________            5    0.04            7    0.04            9    0.16           12    0.16           14    0.01           19    0.01           21    0.16           11    0.16            8    0.04           24    0.16           23    0.16           16    0.16           17    0.04            6    0.01           10    0.01            1    0.04            2    0.04    ______________________________________

D. Composition Examples

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic or topical administration towarm-blooded animals in accordance with the present invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

EXAMPLE 14

Oral solutions

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate aredissolved in 4 l of boiling purified water. In 3 l of this solution aredissolved first 10 g of 2,3-dihydroxybutanedioic acid and thereafter 20g of the A.I. The latter solution is combined with the remaining part ofthe former solution and 12 l of 1,2,3-propanetriol and 3 l of sorbitol70% solution are added thereto. 40 g of sodium saccharin are dissolvedin 0.5 l of water and 2 ml of raspberry and 2 ml of gooseberry essenceare added. The latter solution is combined with the former, water isadded q.s. to a volume of 20 l providing an oral solution comprising 5mg of the A.I. per teaspoonful (5 ml). The resulting solution is filledin suitable containers.

EXAMPLE 15

Capsules

20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 g lactose,0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearate arevigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I..

EXAMPLE 16

Film-coated tablets

Preparation of tablet core

A mixture of 100 g of the A.I., 570 g lactose and 200 g starch is mixedwell and thereafter humidified with a solution of 5 g sodium dodecylsulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water. The wetpowder mixture is sieved, dried and sieved again. Then there are added100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil.The whole is mixed well and compressed into tablets, giving 10.000tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methyl cellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concentrated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

We claim:
 1. A method of treating 5-HT₃ -mediated disorders whichcomprises administering to subjects suffering from 5-HT₃ -mediateddisorders an effective amount of a compound of the formula: ##STR16## apharmaceutically acceptable acid addition salt form or astereochemically isomeric form thereof, wherein:R¹ and R² representhydrogen; n represents 2, 3 or 4; R³ represents hydrogen or methoxy; mrepresents 1 or 2; R⁴ represents hydrogen, amino or C₁₋₃alkylcarbonylamino; and R represents hydrogen or halo.
 2. A methodaccording to claim 1, wherein R³ represents methoxy and has thecis-configuration.
 3. A method according to claim 2, wherein thecompound is laevo-rotatory.
 4. A method according to claim 1, whereinthe compound is (-)-cis-4-amino-5-chloro-2,3-dihydro-N- 1- 3-(3,4-dihydro-4-oxo-2-pyrimidinyl)amino!propyl!-3-methoxy-4-piperidinyl!-2,2-dimethyl-7-benzofurancarboxamideor (-)-cis-4-amino-5-chloro-N- 1- 2-(3,4-dihydro-4-oxo-2-pyrimidinyl)amino!ethyl!-2,3-dihydro-3-methoxy-4-piperidinyl!-2,2-dimethyl-7-benzofurancarboxamide,or a pharmaceutically acceptable acid addition salt form thereof.
 5. Themethod of claim 1, wherein the 5-HT₃ mediated disorder is selected fromthe group consisting of anxiety, psychosis, depression, schizophrenia,cognitive disorders, drug abuse, migraine, emesis and irritable bowelsyndrome.
 6. The method of claim 2, wherein the 5-HT₃ mediated disorderis selected from the group consisting of anxiety, psychosis, depression,schizophrenia, cognitive disorders, drug abuse, migraine, emesis andirritable bowel syndrome.
 7. The method of claim 3, wherein the 5-HT₃mediated disorder is selected from the group consisting of anxiety,psychosis, depression, schizophrenia, cognitive disorders, drug abuse,migraine, emesis and irritable bowel syndrome.
 8. The method of claim 4,wherein the 5-HT₃ mediated disorder is selected from the groupconsisting of anxiety, psychosis, depression, schizophrenia, cognitivedisorders, drug abuse, migraine, emesis and irritable bowel syndrome.